Hepatitis C virus (herein after also referred to as HCV) infection is estimated to afflict about 100 million to 200 million persons around the world, and around 1.5 million to 2.0 million persons in Japan. The infection in about 50% of the infected persons progresses to chronic hepatitis, and 20% of them develop cirrhosis and/or liver cancer thirty years or more after the infection. Hepatitis C is considered to account for about 90% of cases of liver cancer. In Japan, not less than 20,000 patients each year die from liver cancer due to HCV infection.
HCV is a single-stranded RNA virus, classified in the Hepacivirus genus in the Flaviviridae family. The HCV particle is 55 to 65 nm in diameter and composed of a core protein, envelope proteins and RNA. This particle adheres to and enters into human hepatocytes and then uncoats and releases RNA. In the hepatocytes, replicates of mRNA and viral gene RNA are synthesized by RNA-dependent RNA polymerase of the virus itself. Based on information of the mRNA, viral structural proteins, protease, helicase, RNA polymerase, etc. are made, virions are formed, transported through the Golgi apparatus to the cell membrane, and released from hepatocytes, and the virus proliferates.
HCV evades the host immune system by an unknown mechanism as yet. Therefore, even when adults with a mature immune system are infected, persistent infections are established in many cases, and these develop into chronic hepatitis, liver cirrhosis, and liver cancer. It is also known that even when the cancer is removed by surgery, many patients have recurring liver cancer due to the inflammation continuously induced in non-cancerous parts.
Currently, the main effective therapies for HCV clearance are combination therapies of interferon (injection) and ribavirin (oral formulation), but they are considered to be directed toward therapies with combinations of compounds having various modes of virus inhibition in future.
Clinical trials have been conducted on combinations of agents having various mechanisms of action targeting the HCV virus, such as protease inhibitors, nucleic acid.non-nucleic acid polymerase inhibitors that inhibit viral nucleic acid synthesis, and NS5A inhibitors, and reports on clinical results indicating high therapeutic performance are gradually increasing. It is considered, based on these findings, that therapeutic methods using combinations of several agents having different modes of inhibition will be established for treatment of hepatitis C in future, as they have been for treatment of HIV.
In administering several agents to patients with hepatitis C, needs for combinations with orally available agents are considered to be higher than combinations with injections in healthcare settings.
In addition, treatment with orally available agent does not require hospitalization of patients, and allows outpatient treatment, greatly reducing burden on patients. It is also considered that outpatient treatment may greatly contribute to the reduction of medical expenses in comparison with hospitalization treatment.
We previously found that viridiofungin derivatives (PTLs 1 and 2), for example, compounds represented by the following formula:
have an inhibitory activity on replication of hepatitis C virus (HCV) and a unique mechanism of action, i.e., serine palmitoyl transferase (SPT) inhibition (PTL3), and they are useful as therapeutic agents for HCV infection. Effective synthetic methods of the compounds and intermediates used for the same are disclosed in PTL4.